Delineation of molecular markers characteristic of premalignant prostate lesions is critically important to effectively control and manage the highly prevalent human prostate cancer. Gene expression profiling of these lesions in relation to normal or cancerous tissues will provide important clues to the etiology of prostate carcinogenesis and help to formulate novel prevention strategies and early detection methods. Systematic gene expression analysis of putative precursor lesions in clinical specimens, however, is lagging behind the intensive molecular characterization in later stages of prostate cancer development. Our long-term goal is to investigate all potential cancer precursor lesions in the human prostate gland and firmly establish the molecular determinants of cancer initiation. Our overall hypothesis is that histological changes preceding, and leading to cancer initiation and progression can be defined by signatory expression profiles, which in turn reflect molecular alterations as a result of multiple genetic and environmental factors. This exploratory study will focus on the molecular characterization and classification of human high-grade prostatic intraepithelial neoplasia (HGPIN), the most probable precursor lesion to prostate cancer, in an effort to identify premalignant prostate markers associated with clinically defined human prostate cancer. We will take advantage of the well-established cDNA microarray technology to systematically profile 60 HGPIN specimens by comparison to lesions representing invasive prostate cancer and normal prostate epithelium. Specifically, we set out to achieve the following Aims in 2 years: (1) To define the molecular signature of HGPIN and identify putative premalignant prostate markers common to all HGPIN lesions or unique to subgroups of HGPIN. (2) To perform immunohistochemical analysis of known prostate cancer/invasion markers and candidate premalignant markers in HGPIN lesions. [unreadable] [unreadable]